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ISSN No:2321 8630, V 1, I 1, 2014

Journal Club for Pharmaceutical Sciences (JCPS)


Manuscript No: JCPS/RES/2014/11, Received on: 02/08/2014, Revised on: 07/08/2014, Accepted on: 11/08/2014

RESEARCH ARTICLE
Formulation Optimization and Evaluation of Orodispersible Tablets of an
Antipsychotic Drug Using Solubility Enhancement Technique
Chauhan KV*1, Kadliya PN1, Patel BA1, Patel KN1, Patel PA1
1
Depatment of Pharmaceutics, Shree Swaminarayan Sanskar Pharmacy College,
Zundal, Gandhinagar, Gujarat, India
ABSTRACT
The main objective of this study is to formulate oro dispersible tablets of Olanzapine and to
complex Olanzapine with -cyclodextrin (-CD) and PVP K 30. Olanzapine is second
generation atypical antipsychotic drug. Phase solubility studies demonstrated that addition of
water soluble polymer PVP K 30 with -CD further enhanced solubility of drug compared to
-CD without PVP K 30. Complex was characterized using infrared spectroscopy,
differential scanning calorimetry, % drug release study, % drug content and saturated
solubility study. A 32 full factorial design was applied to systematically optimize the drug
disintegration time. The concentration of Croscarmellose Sodium (X1) and concentration of
Kyron T 314 (X2) were selected as independent variables. The disintegration time (Y1) and
wetting time (Y2) were selected as dependent variables. The prepared tablets were evaluated
for hardness, friability, disintegration time, wetting time and In-vitro drug release. The
different formulations showed disintegration time between 19 to 48 seconds. The results
indicated that concentration of croscarmellose Sodium (X1) and concentration of Kyron T
314 (X2) significantly affected the disintegration time (Y1) and wetting time (Y2).Regression
analysis and numerical optimization were performed to identify the best formulation.
Formulation F18 prepared with Croscarmellose Sodium (4.47 %) & Kyron T 314 (3.73 %)
was found to be the best formulation with disintegration time 20 sec, wetting time 26 sec and
% drug release in 10 min 99.49%.
KEYWORDS
Olanzapine, Orodispersible tablet, -cyclodextrin, Croscarmellose sodium, Kyron T 314,
Disintegration time, Wetting time, 32full factorial design
INTRODUCTION

forms is Dysphagia or difficulty in

Introduction to Drug Delivery System

swallowing for many patients; however,

The oral route remains the preferred route

hand

for administration of therapeutic agents.

underdeveloped muscular and nervous

One important drawback of such dosage

systems in young individuals, children and

tremors,

geriatric

patients,

the

in case of uncooperative patients, the


*Address for Correspondence:
Krishna V. Chauhan,
Department of Pharmaceutics, Shree
Swaminarayan Sanskar Pharmacy College,
Zundal, Gandhinagar, Gujarat, India.
E-Mail Id: krishna_chauhan0123@yahoo.in

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problem

of

swallowing

is

common

phenomenon. For example, a very elderly


patient may not be able to swallow a daily
dose of antidepressant; a schizophrenic

33

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

patient can hide a conventional tablet

with dysphagia are not able to swallow

under his or her tongue to avoid its daily

conventional Olanzapine tablet.

dose of an atypical anti-psychotic. Orally

To overcome this problem an attempt was

disintegrating tablets (ODTs) are a perfect

made

fit for all these patients.

ODTsinclusion

to

complex

formulate

of

and

evaluate

complex.
Olanzapine

Inclusion
with

The Center for Drug Evaluation and

cyclodextrin was made to improve the

Research (CDER), US FDA defined Oral

aqueous solubility of Olanzapine and to

Disintegrating Tablets (ODT) as A solid

enhance dissolution rate of Olanzapine. It

dosage

medicina

may enhance the pregastric absorption of

lsubstances, which disintegrates rapidly,

Olanzapine. -cyclodextrin may act as

usually within a matter of seconds, when

channel forming agent because it helps in

placed upon the tongue.

quick disintegration of tablets and may act

Olanzapine is second generation atypical

as permeation enhancer to pass Olanzapine

antipsychotic

through

form

containing

drug

classified

as

oral

mucosa.

Tablets

were

thiobenzodiazepines. It is D2 and 5 HT2

prepared by using -cyclodextrin and four

receptor antagonist mainly used drug used

super disintegrants, namely as SSG,

in the treatment of schizophrenia and

croscarmellose sodium, crospovidone and

bipolar disorder. In this type of disease

Kyron T 314. Super disintegrants are

require rapid onset of action in order to

added to facilitate drug release and

control on mental condition.

It is

consequently improve the solubility of

practically insoluble in water, having only

Olanzapine. Tablets were prepared by

60%

Olanzapine

using direct compression technique. The

undergoes extensive first pass metabolism.

simplicity and cost effectiveness of the

It has less extra pyramidal side effects

direct

compared to other antipsychotics.Further,

positioned

Olanzapine has a small dose, optimum

alternative to granulation technologies.

oral

bioavailability.

molecular weight, unionized at salivary pH


and a long elimination half life (21-54

compression
direct

technique

compression

have
as

an

MATERIALS & METHODS


Experimental Work

hour).Some schizophrenic patients hide a


conventional tablet under their tongue to

Materials

avoid its daily dose of an atypical

Olanzapine and other excipients were

antipsychotic. Also schizophrenic patients

gifted

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from

West-Coast

Pvt.

Ltd.,

34

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Ahmedabad, Avicel pH 112 and Mannitol


SD 200 were gifted from Torrent Research

appropriately

diluted.

The

OLP

concentration was determined using a UV


visible spectrophotometer in 226.8 nm.

Centreand Kyron T 114 was gifted by


Corel Pharma Chem., Ahmadabad.

Experiments were performed in triplicate.


The graph was plotted against drug
concentration

DRUGEXCIPIENTS

vs.

betacyclodextrin.
COMPATIBILITY STUDY

determined

by

FT-IR

The

blanks

of
were

prepared using the same concentration of

Compatibility of the drug with excipients


was

concentration

spectral

betacyclodextrin with or without water


soluble polymer in distilled water so as to
cancel out any absorbance that may be

analysis, this study was carried out to


detect

any

changes

on

chemical

constitution of the drug after combined it

exhibited by betacyclodextrin.
Preparation of Inclusion Complex
Kneading Method
Required quantities of the Olanzapine and

with the excipients. The samples were


taken for FT-IR study.

and 1:4 molar ratios and thoroughly mixed


with or without water soluble polymer. A

Methods
Phase Solubility Analysis for Olanzapine
Phase solubility studies were performed
according to the method reported by
Higuchi and Connors.Various aqueous
solutions (0.2%, 0.4%, 0.6%, 0.8% and 1%
w/v) of the betacyclodextrin was prepared
with and without water soluble polymer
PVP K 30 and PEG 4000( 5% w/v) and
10 ml of these solution, excess quantities
of Olanzapine (20 mg) were added. The
solutions were kept for shaking for 24 h
using

lab

-CD were weighed to give 1:1, 1:2, 1:3

shaker.

After

complete

equilibration the supernatant solution were


collected carefully and filtered using
Whatman filter paper (No. 41) and

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homogeneous paste of Olanzapine and CD was prepared by adding water: ethanol


(50: 50) in small quantities. The paste was
kneaded for 60 min and dried in hot air
oven at 45-50C. The dried complex was
sieved through 60# and evaluated. The
optimized complex was further prepared
by addition of water soluble polymer PVP
K 30. It was added at a concentration of
5%, 10% and 15% of the solid complex.
Characterization of Complex
Inclusion complex was characterized and
evaluated using following techniques.
Fourier

Transform

Infrared

(FTIR)

Spectroscopic Analysis

35

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

The Fourier transform infrared spectrum of

and 50 rpm in Phosphate buffer (pH 6.8).

moisture

of

At fixed time intervals, 10 ml aliquots

Olanzapine, -CD, PVP K 30 and kneaded

were withdrawn, filtered, suitably diluted

complex

IR

and then assayed for Olanzapine content

spectrophotometer by potassium bromide

by measuring the absorbance at 226.8 nm.

(KBr) pellet method.

Fresh media (10 ml), which was pre-

Differential Scanning Calorimetry (DSC)

warmed at 37 C, was replaced in to the

Analysis

dissolution medium after each sampling to

DSC scans of the powdered samples were

maintain its constant volume throughout

recorded. The thermal traces were obtained

the

by heating the complex from 40 to 350 C

performed in three replicates (n = 3), and

at heating rate of 10 C under inert

calculated mean values of cumulative drug

nitrogen

release were used while plotting the

free

powdered

recorded

dynamic

sample

on

atmosphere

(100

test.

Dissolution

studies

ml/min) in open aluminium crucibles.

release curves.

Drug Content Estimation 7

Saturation Solubility Study

Olanzapine

betacyclodextrin

were

complex,

Saturation solubility study was performed

equivalent to 10 mg of drug, was weighed

according to method reported by Higuchi

accurately and added to 100 ml volumetric

and

flask. To this solution add small amount of

inclusion complex were added to 25 mL

ethanol. These solutions were stirred for

distilled water in glass stoppered conical

60 mi, till the entire drug leached out then

flasks and shaken for 24 h in rotary flask

make the volume up to mark with

shaker. After shaking the solutions were

phosphate buffer 6.8. Then this solution

filtered through Whatman filter paper No.

was filtered. 0.5 ml of solution withdrawn

41.

and added into 10 ml of volumetric flask

spectrophotometrically at 226.8 nm. Each

and volume was made to 10 ml (5 m/ml)

sample was done in triplicate.

Connors.

The

Excess

filtrate

quantities

was

of

analyzed

with phosphate buffer pH 6.8. Drug


content was estimated by UV visible

Formulation and Evaluation of Tablets

spectrophotometer at 226.8 nm using

Selection of super disintegrant

phosphate buffer pH 6.8 as blank.

In preliminary trial batches, different

Dissolution Study6, 7

concentrations i.e. 2 and 4% of Sodium

Dissolution studies were carried out using

starch glycolate (SSG), Crospovidone

a USP dissolution apparatus type II with

(CP), Croscarmellose sodium (CCS) and

900 ml dissolution mediums at 37 C 0.5

Kyron T 314 were screened. From the all

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36

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

the four super disintigrants CCS and


Kyron T 314 had shown less disintegration

Bulk density =Weight of the powder /


Volume of the packing

time and wetting time compared to SSG


Tapped Density

and CP.
Method - Direct Compression Method

Weighed quantity of powder blend was

According to the formula given in table1

taken into a graduated cylinder and volume

all the ingredients (without magnesium

occupied by powder blend was noted

stearate and aerosil) were passed through

down. Then cylinder was subjected to 500,

#40 mesh separately. Required quantity of

750 and 1250 taps in tap density tester

each excipient was weighed accurately and

According to USP the blend was subjected

blend was mixed thourouly. Lubricants i.e.

to 500 taps. The %volume variation was

aerosil and magnesium stearate were

calculated and subjected for additional 750

passed through 80# and mixed them to

taps and %volume variation is calculated.

above

Tapped density= Weight of the powder /

blend.

Powder

blend

was

compressed using 9 mm concave punch on

volume of the tapped packing

rotary tablet machine.


Evaluation Parameters of Powder Blends
Orally

disintegrating

tablets

are

manufactured by several processes but for


all of them, first a blend of various
ingredients (APIs and excipients) is made.
The quality of tablet, formulated is
generally depending upon the quality of

Carrs compressibility index


The compressibility index of the blends
will

be

determined

by

Carrs

compressibility index.
Carrs compressibility index (%) =
Carrs compressibility index (%) =
Tapped density-Bulk density X 100

physicochemical properties of blends.


Tapped density

There are many formulation and process


variables involved in mixing and all these
can affect the characteristics of blends

Hausner's ratio

produced. The various characteristics of

Hausner's ratio is an index of ease of

blends tested are as given below.

powder flow. It is calculated by following

Bulk density
Apparent bulk density was determined by
pouring 10 gm of powder blend into
graduated cylinder and measuring the

formula.
Hausner's ratio = Tapped density / Bulk
density

volume.

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37

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Angle of repose

weight tablets were being made. Twenty

Angle of repose () is a measure of

tablets were selected randomly from each

flowability of material. It was determined

formulation, weighed individually and the

using fixed height funnel method. A glass

average weight and % variation of weight

funnel was placed with its tip positioned at

was calculated.

a fixed height (h) above a graph paper on a

Disintegration Time

horizontal surface. The blend was poured

The USP device to test disintegration has

through a funnel until the apex of conical

six glass tubes that are 3 long, open at the

pile touched the tip of the funnel. The

top, and held against 10 screen at the

radius of the pile (r) was measured and

bottom end of the basket rack assembly.

angle of repose was calculated as follows.

One tablet is placed in each tube and the

= tan-1 (h/r)

basket rack is poisoned in 1 liter beaker of


distilled water at 37 2 C, such that the

Where, = angle of repose

tablets remain below the surface of the

h = height of the pile

liquid on their upward movement and

r = average radius of the powder cone

descend not closer than 2.5cm from the

Evaluation of Tablets

bottom of the beaker. The time required to

Thickness
The

thickness

of

the

tablets

was

obtain complete disintegration of all the


tablets will be noted.

determined using a vernier caliper.


Hardness
Hardness

was

measured

using

the

Monsanto hardness tester. Measure the


pressure required to break diametrically
placed matrix tablet, by a coiled spring. It
is expressed in kg/cm2.
Friability
Friability of the tablets was determined
using Roche friabilator. It is expressed in
%
Weight Variation
It was performed as per the method given
in the Indian pharmacopoeia. Tablets were
randomly checked to ensure that uniform

Wetting Time
A small piece of tissue paper folded twice
will be placed in a small petridish
containing 6ml of water. A tablet will be
put on the paper and the time required for
complete wetting was measured.
% Drug Content7
Three tablets were accurately weighed and
finely powdered. A quantity equivalent to
10 mg of Olanzapine was transferred to a
100 ml volumetric flask. To it, 50 ml of
ethanol was added and shaken for 1 hour
to dissolve drug. The solution was filtered
and residue was washed with 25 ml of

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38

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

ethanol. The washing obtained was added

each at 3 levels, and experimental trials

to initial filtrate and volume was made up

were

to 100 ml with ethanol. From above

combination. In the preliminary trial runs,

solution 0.5 ml of stock solution was

5 % Cross carmalose sodium and 4 % of

diluted to 100 ml of phosphate buffer pH

Kyron T 314 showed good results. So

6.8. The drug content was determined

these levels were selected and subjected to

spectrophotometrically at 226.8 nm.

further

Dissolution Studies 7

sodium and Kyron T 314were selected as

Dissolution studies were carried out for all

independent factors whereas disintegration

the formulation combinations in triplicate,

time (DT) and wetting time (WT) were

employing USP XXIII paddle method

measured as responses. The polynomial

(Apparatus 2) using phosphate buffer pH

equation can be used to draw conclusions

6.8, as the dissolution medium (900 ml) at

after

50 rpm and 37 0.5C. An aliquot of

coefficient and the mathematical sign. The

sample was periodically withdrawn at

responses were analyzed for ANOVA

suitable

volume

using Design Expert version 8.0.5. A

replaced with equivalent amounts of plane

mathematical equation was generated for

dissolution medium. The samples were

each

analyzed spectrophotometrically at 226.8

mathematical models were tested for

nm.

significance. Response surface plots were

Full Factorial Design

generated for each response to study the

A 32 Factorial design was chosen for the

behaviour of the system.

time

intervals

and

performed

at

all

optimization.

considering

response

possible

Cross carmalose

the

magnitude

parameter.

of

The

current formulation optimization study. In


this design two factors were evaluated,

Table 1: Selection of Levels for Independent Variables and Coding of Variable


INDEPENDENT VARIABLES
Levels

Coded value

Low

X1 (%)

X2 (%)

-1

Intermediate

High

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39

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Table 2: Factorial Design Layout and Data Transformation for Factorial Batches
Run

Independent

Independent Variable in

Variables in

actual form

Dependent variable

coded form
Factor

Factor

Cross

Kyron T

Disintegration

Wetting

carmalose

314

Time (Sec.)

Time (Sec.)

sodium
1

-1

-1

480.35

540.52

-1

330.42

390.56

-1

290.39

350.43

-1

410.45

490.49

280.58

330.39

240.65

300.32

-1

340.43

400.46

230.59

290.39

190.52

250.78

Table 3: Formulations using 32Factorial Design


FORMULATION

F1

F2

F3

F4

F5

F6

F7

F8

F9

Olanzapine --CD PVP K

130.

130.

130.

130.

130.

130.

130.

130.

130.

30 complex

88

88

88

88

88

88

88

88

88

Croscarmellose sodium

2.5

2.5

2.5

7.5

7.5

7.5

12.5

12.5

12.5

Kyron T 314

10

10

10

Microcrystalline cellulose

50

50

50

50

50

50

50

50

50

Aspartame

1.25

1.25

1.25

1.25

1.25

1.25

1.25

1.25

1.25

Aerosil

1.25

1.25

1.25

1.25

1.25

1.25

1.25

1.25

1.25

Mg stearate

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Mannitol SD 200

61.

56.

51.

56.

51.

46.

51.

46.

41.

62

62

62

62

62

12

62

62

62

INGREDIENTS

pH 112

Total Weight

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250(mg/tablet)

40

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Validation of statistical model

validate RSM. The tablets were formulated

From overlay plot of responses, optimized

using chosen optimal composition &

formulation was selected as checkpoint to

evaluated for DT & WT.

Table 4: Composition of Optimized Formulation


FORMULATION INGREDIENTS

F10

Olanzapine--CD-PVP K 30 complex

130.88

MCC PH 112

50

Croscarmellose sodium

11.17

Kyron T 314

9.32

Aspartame

1.25

Aerosil

1.25

Magnesium stearate

2.5

Mannitol up to.

250 mg

Stability Study of Optimized Batch

between 50 and 100. The dissolution

Stability study was carried out for the

profiles

optimized formulation for 25 2oC/ 60 5

following formula,

of products

were

compared

% RH and 40 2oC/ 75 5 % RH for 1

months and samples were withdrawn at the

f2 = 50 x log {[1+(1/n) | Rj Tj | 2 ] -

end of 0, 1, 2, 3 and 4 week and evaluated

0.5 x 100}

for active drug content, disintegration

j=1

time, wetting time and Invitro drug release.

Where,

Comparison of Optimized Formulation

n = number of time points

with Market Product Using Similarity

Rj = Dissolution value of the reference

Factor (f2)

batch at

The similarity factor (f2) given by SUPAC

time t

guidelines for modified release dosage

Tj = Dissolution value of the test batch at

form was used as a basis to compare

time t.

dissolution profile. The dissolution profiles


are considered to be similar when f2 is

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RESULT AND DISCUSSION


Identification of Drug by FT - IR

41

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Fig 1: FTIR Spectra of Olanzapine

Drug-Excipients Compatibility Study by


FT - IR
Fig 2: FTIR Spectra of Olanzapine and Excipients

A Drug + Sodium starch glycolate

FTIR

spectra

of

Olanzapine

show

E Drug + Kyron T 314

characteristic bands are attributed to the

B - Drug + Crosspovidone

stretching of different group vibrations:

F Drug+ MCC pH 112

3247.27 cm-1 stretching of the N-H band

C Drug + Croscarmellose sodium

2930.2 cm-1 stretching of the N-H band

G Drug + Mannitol SD 200

1586.16 cm-1 stretching of the C=C band


1290.14 cm-1 stretching of the C-N band
759.81 cm-1 band due to O-disubstituated

Interpretation
To study the compatibility of drug with

benzene

excipients

The IR spectrums of Olanzapine and its

IR

spectra

of

drug

in

combination with excipients in 1:1 ratio

combination

was studied prior to preparation of

croscarmellose, etc. were shown in Figures

Olanzapine orally disintegrating tablets.

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indicate

with

that

crospovidone,

there

was

no

42

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

physicochemical interaction in between

characteristics bands were presented in

drug and studied excipients because all

physical mixture.

Phase Solubility Study

Conc. of Olanzapine(mg/ml)

Fig 3: Phase Solubility of Olanzapine


0.004
0.0035
0.003

y = 0.1796x + 0.0017
R = 0.977

y = 0.2069x + 0.0018
R = 0.9608

0.0025
0.002
0.0015
0.001
0.0005

y = 0.172x + 0.0017
R = 0.9926

-CD
-CD with
PVP K 30

0
0

0.002 0.004 0.006 0.008


Concentration of -CD(mg/ml)

-CD with
PEG 4000

0.01

From the Phase solubility analysis it was

Characterization

concluded that as the concentration of

cyclodextrin-PVP K 30 Complex

betacyclodextrin increased concentration

Drug Content Estimation

of Olanzapine is also increased. According

The drug content of inclusion complex

to Higuchi and Connors, the obtained

prepared by kneading was found 94.44

curve was AL type of solubility curve.

%1.25to 97.25 % 1.10.

Addition of the water soluble polymer like

Saturation Solubility Study

PVP

In the present work, enhancement in the

30

and

PEG

4000

with

Olanzapine--

betacyclodextrin solubility of the drug was

solubility

further increased. The stability constant

inclusion complex. Solubility of pure

was found to be 122.19, 128.77 and 144.93

Olanzapine was found to be 0.03432.45

for -CD, -CD with PEG 4000 and -CD

mg/mL and solubility of complex was

with PVP K 30 respectively. From the

found to be 0.07653.36mg/mL.

graph it was concluded that solubility of

Fourier

the drug higher in case of PVP K 30

Spectroscopy

compare to PEG 4000. So PVP K 30 was

IR is a highly sensitive method of analysis,

selected

all spectra of complex showed some or

for

the

preparation

of the

complex.

was

of

observed

Transformation

in

case

of

Infrared

other changes from parent spectra (Figure


3). 3247.27 cm-1 stretching of the N-H

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43

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

band, 2930.2 cm-1 stretching of the N-H

influenced

band, 1586.16 cm-1 stretching of the C=C

Absorption band at 3247.27 cm-1

band, 1290.14 cm-1 stretching of the C-N

completely disappeared in the complex

band 759.81 cm-1 band due to O-

spectra, which indicate that hydrogen bond

disubstituated benzene.

formation between hydroxyl group of

In

the

FTIR

spectra

of

by

complex

formation.
is

prepared

betacyclodextrin, PVP K 30 and amine

complexes, Olanzapine bands are almost

group of the drug. Reduction in intensity

completely obscured by very intense and

of the C=C band at 1586.16 cm-1.

broad CD bands, which are hardly

Fig 4: FTIR Spectra of (a) Drug (b) -CD (c) PVP K 30 (d) Physical mixture and (e)
Complex

Differential Scanning Calorimetry

130 C, which are related to evaporation of

Olanzapine

characteristic

water from the cyclodextrin. -CD also

196.50C,

shows small endo or exo effects at 297

corresponding to the Olanzapine melting

320 C due to thermal degradation. In

point and indicating that the drug is in a

DSC thermogram of Olanzapine- CD-

crystal polymorphic form. Furthermore, -

PVP K 30 Complex peak were disappeared

CD and PVP K 30 showed broad

which gave conformation of complex

endothermic

exhibited
peak

a
at

endothermic events in the range from 80 to

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44

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Fig 4: DSC Thermogram of (A) Olanzapine (B) Betacyclodextrin (C) PVP K 30 and (D)
Complex

Fig 5: Comparative Dissolution Profiles of Various Molar Ratios of Olanzapine--CD

% CDR

Complex
100
90
80
70
60
50
40
30
20
10
0

drug
1:1 M
1:2 M
1:3 M
1:4 M
0

10

20

30

40

50

60

Time (mins.)

Dissolution Study of Olanzapine and its

release compare to other molar ratios. So it

Inclusion Complex

was selected for the further preparation of

Based on the % CDR 1:3 M of the drug to

complex with PVP K 30.

betacyclodextrin was shown higher % drug

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45

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Fig 6: Comparative Dissolution Profiles of Various Molar Ratios of Olanzapine--CDPVP K 30


100

% CDR

80
1:3 M

60

PVP K 30 - 5%

40

PVP K 30 - 10%

20

PVP K 30 - 15 %

0
0

10

20
30
Time (mins.)

40

50

60

Based on % drug release from different

K 30 was optimized. The increase in the

molar ratios of complex Olanzapine: -

dissolution of Olanzapine with -CD and

cyclodextrin, 1:3 molar ratio with 10 %

PVP K 30 could be explained by the

PVP K 30 was selected as optimized ratio

principal

as it was shown 99.31 % drug release in 30

complex formation and the amorphous

min as compared to 1:3 with 5 % PVP K

form generation of Olanzapine. The high

30 molar ratio that was shown 99.50 %

solubility of -CD and PVP K 30 in water

release at the end of 60 min. 1:3 molar

resulted in better wettability of drug

ratio with 15 % PVP K 30was not shown

particles and local enhancement of its

significant increase in% drug release when

solubility

compare to 1:3 molar ratio with 10 % PVP

surrounding the drug particles.

of

at

hydrophilicity,

the

inclusion

diffusion

layer

K 30. So, 1:3 molar ratio with 10 % PVP

Table 5: Pre-Compression Evaluation Parameters of Powder Blend of Factorial Batches


Batch Code

Bulk
Density
(gm/ml)

Tapped
Density
(gm/ml)

Carrs
index
(%)

0.4410.032
0.4950.038
13.200.32
F1
0.4820.025
0.5520.019
12.720.13
F2
0.4900.017
0.5600.029
13.500.15
F3
0.4750.018
0.5390.09
12.320.29
F4
0.4800.010
0.5650.015
14.280.32
F5
0.4920.013
0.5540.023
12.910.19
F6
0.5030.017
0.5760.010
12.400.19
F7
0.4690.029
0.5370.016
13.200.15
F8
0.4760.019
0.5290.024
12.820.09
F9
All values are expressed as mean standard deviation, n=3

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Angle of
repose
( )

Hausners
ratio

27.30.21
29.40.22
28.70.13
27.60.22
26.4030

1.130.29

27.80.18
27.10.25
26.20.22
27.30.15

1.140.19
1.140.16
1.120.14
1.160.25
1.120.20
1.140.16
1.150.13
1.120.10

46

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Evaluation of Powder bland

and angle of repose ranged from 26.2 to

The powder blend for all nine formulations

29.4 . All these results indicate that, the

were evaluated for bulk density which

power blend possess good flowability and

ranged from 0.441 to 0.503, tapped density

compressibility properties. Hence, tablets

which ranged from 0.529 to 0.576, Carrs

were prepared using direct compression

index ranged

method.

from 12.32 to

14.28,

Hausners ratio ranged from 1.12 to 1.16

Evaluation of Tablets

Table 6: Physical Evaluation Parameters of Tablets of factorial batches


Batch

Weight

Hardness

Thickness

Friability

Drug Content

Code

Variation

(kg/cm2)

(mm) SD

(%)SD

(%) SD

(mg)SD,

SD

n=20
F1

Pass

3.2 0.23

4.950.02

0.480.02

99.481.15

F2

Pass

3.5 0.52

4.93 0.03

0.420.01

99.211.23

F3

Pass

3.4 0.29

4.950.02

0.370.04

99.671.73

F4

Pass

3.1 0.52

4.930.04

0.560.03

98.321.33

F5

Pass

3.5 0.59

4.970.01

0.490.01

98.531.39

F6

Pass

3.3 0.26

4.950.03

0.410.03

98.561.20

F7

Pass

3.5 0.52

5.150.02

0.390.02

99.141.31

F8

Pass

3.1 0.53

4.950.01

0.340.01

99.781.30

F9

Pass

3.2 0.28

4.930.02

0.460.03

98.231.14

All values are expressed as mean standard deviation, n=3


All the tablet preparations were evaluated

weight

for various physical parameters before

pharmacopoeial limits of 5% of the

proceeding further. Table 6 includes the

weight. The weights of all the tablets were

values (mean SD) of weight variation,

found to be uniform with low standard

hardness, thickness and friability of eight

deviation values.

tablet batches prepared using different

Thickness of all tablets was in the range

combinations of functional excipients. All

between 4.93 mm to 5.15 mm. Hardness of

the eight batches passed weight variation

tablets was in range between 3.1 to 3.5

test. All the formulated (F9 to F17) tablets

kg/cm2.Friability was in range between

passed weight variation test as the %

0.34 to 0.56 %. Thus, all the physical

Copyright reserved by Journals Club & Co.

variation

was

within

the

47

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

parameters of the manually compressed

was observed in batches prepared using

tablets were quite within control. Friability

combination of CCS and Kyron T 314. As

values were less than 1 % in all cases

CCS combined with Kyron T 314, by

shows good mechanical strength at the

keeping concentration of CCS constant

time of handling and transports.

and increase concentration of Kyron T 314

The % drug content for tablets of all

from 0 to 4%, disintegration time was

formulation was found to be in the range

decreased as shown in result.

of 98.23 to 99.67%. Thus the assay of

The wetting time of tablets as shown in

Olanzapine was found to be quite within

Table 2 of all nine formulations was in the

the range.

range of 26 to 54 seconds. The wetting

The results shown in Table 2indicated that

time is closely related to the disintegration

concentration-dependent

time.

disintegration

Fig 7: Effect of Super disintegrants on Dissolution Profiles of Factorial Batches


(F1-F9)
100

% CDR

90
80

F1

70

F2

60

F3

50

F4

40

F5

30

F6

20

F7

10

F8

F9
0

10

15

20

25

30

Time(mins.)

The dissolution profiles of all the nine

3% and4 % Kyron T 314 was shown 94.52

formulations are shown in Figure 6.17.

and 99.09 % in 10 minutes. Combination

From graph it was concluded that as the

of

concentration

disintegrant

dissolution rate as compared to individual

increases, % drug release was also

super disintegrant. The release of drug was

increased. % drug release from F8 and F9

largely depended on the disintegration

of

super

two

disintegrates

also

improves

formulations prepared with CCS 5 % and

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48

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

time. That is faster the disintegration of

Positive sign in front of terms indicate

tablets, better and faster is the release.

synergistic effecy while negative indicate

Factorial

antagonistic effect upon responses. So,

equation

for

Dependent

sign of b1 andb2 were negative shows that

Variables

as a concentration of CCS and Kyron T


1) Factorial equation for Disintegration

314 increases ,WT decreases. As the R2

Time

value nearer to 1 indicate selected model

Y= 27.89 5.50 X1 -8.33X2 +1.25X1X2 -

was significant.

0.17 X12 + 4.67 X22, R2= 0.9940

ANOVA for Quadratic Model for DT and


WT

Positive sign in front of terms indicate

ANOVA

synergistic effect while negative indicate

table

used

to

generate

mathematical models. The high values of

antagonistic effect upon responses.So, sign

correlation coefficient for DT and WT

of b1 andb2 were negative shows that as a

indicate a good fit i.e.good agreement

concentration of CCS and Kyron T 314

between the dependent and independent

increases , DT decreases. As the R2 value

variables. The mathematical model was

nearer to 1 indicate selected model was

evolved by omitting insignificant term (p

significant.

>0.05). So, the main effect X1 & X2 were

2) Factorial equation for Wetting Time

found significant as p value was < 0.05.

Y= 33.11 -5.67 X1 -8.67 X2 +1.25 X1X2


0.67X2 + 6.33 X22, R2= 0.9965

Table 7: ANOVA Response Surface Quadratic Model for Disintegration Time


p-value

Source

SS

df

MS

F Value

Model

648.03

129.61

451.53

0.0002

A CCS

181.50

181.50

632.32

0.0001

B-Kyron T 314

416.67

416.67

1451.61

<0.0001

AB

6.25

6.25

21.77

0.0186

A2

0.056

0.056

0.19

0.6897

B2

43.56

43.56

151.74

0.0012

Cor Total

648.89

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prob > F

R2

0.9987

49

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Table 8: ANOVA Response Surface Quadratic Model for Wetting Time


F

p-value

Value

prob > F

146.14

199.78

0.0006

192.67

263.39

0.00057

450.67

450.67

616.10

0.0007

AB

6.25

6.25

8.54

0.0613

0.89

0.89

1.22

0.3508

B2

80.22

80.22

109.67

0.0019

Cor Total

732.89

Source

SS

df

MS

Model

730.69

A - CCS

192.67

B-Dilution ratio

R2

0.9970

square (MS) to the appropriate error (i.e.


ANOVA Table shows the results of the

residual) mean square. The mathematical

analysis of variance (ANOVA), which was

model

used to generate mathematical models. The

insignificant term (p > 0.05). So, the main

high values of correlation coefficient for

effect X1 & X2 were found significant as p

DT and WT indicate a good fit i.e. good

value was < 0.05.

agreement between the dependent and

Response Surface Plots

independent variables. The F value in the

Effect of X1 and X2 on Disintegration

ANOVA table is the ratio of model mean

Time

was

evolved

by

omitting

Fig 8: Two-Dimensional Contour Curve for Disintegration Time


Design-Expert Software
Factor Coding: Actual
DT
Design Points
48

DT

4.00

Prediction

20

21.024

3.00

B: Kyron T 314

X1 = A: CCS
X2 = B: Kyron T 314

2.00

30

1.00

40

0.00
1.00

2.00

3.00

4.00

5.00

A: CCS

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50

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Fig 9: 3-D graph showing effect of CCS and Kyron T 314 on Disintegration Time (R1)
Design-Expert Software
Factor Coding: Actual
DT
Des ign points above predicted value
Des ign points below predicted value
48

21.024

20
X1 = A: CCS
X2 = B: Kyron T 314

50
40

DT

30
20
10

5.00

4.00

4.00
3.00
3.00
2.00

B: Kyron T 314

A: CCS

2.00

1.00
0.00

1.00

This contour plot shows the effect of

of X1 and X2 increases, the value of

concentration of croscarmellose (X1) and

response Y1 decreases.

concentration

Effect of X1 and X2 on Wetting Time

of

kyron

314

on

disintegration time (Y1). As concentration

Fig 10 : Two-Dimensional Contour Curve for Wetting Time


Design-Expert Software
Factor Coding: Actual
WT
Design Points
54

WT

4.00

Prediction

26

26.636

3.00

B : K yron T 314

X1 = A: CCS
X2 = B: Kyron T 314

30
2.00

1.00

40

50
0.00
1.00

2.00

3.00

4.00

5.00

A: CCS

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51

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Fig 11 : 3-D graph showing effect of CCS and Kyron T 314 on Wetting Time (R1)
Design-Expert Software
Factor Coding: Actual
WT
Des ign points above predicted value
Des ign points below predicted value
54

26.636

26
X1 = A: CCS
X2 = B: Kyron T 314

60
50

WT

40
30
20
5.00
4.00
4.00
3.00
3.00
2.00

A: CCS

2.00

1.00

B: Kyron T 314
0.00

1.00

This contour plot shows the effect of

time (Y2). As concentration of X1 and X2

concentration of croscarmellose (X1) and

increases, the value of response Y2

concentration of kyron T 314 on wetting

decreases.

Fig 12 : Overlay Plot of Response Variables


Design-Expert Software
Factor Coding: Actual
Overlay Plot

Overlay Plot

4.00

DT
WT
Design Points

DT:
WT:
X1
X2

3.00

B : K yro n T 3 1 4

X1 = A: CCS
X2 = B: Kyron T 314

21.024
26.636
4.47
3.73

WT: 26.000

2.00

WT: 35.000
DT: 30.000

1.00

0.00
1.00

2.00

3.00

4.00

5.00

A: CCS

From overlay plot of responses, optimized

concluded that by adopting systemic

formulation was selected as checkpoint to

formulation approach one can reach to an

validate RSM. The Overlay plot of

optimum point in shortest time with

responses generates an optimized area as

minimum effect. Thus, we can conclude

per desired criteria of DT should be 20 sec

that statistical model is mathematically

& WT should be 25 sec. So, it can be

valid.

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52

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Table 9: Evaluation Parameters of Optimized Formulation


PRECOMPRESSION EVALUATION PARAMETERS
Bulk density(gm/ml)

Bulk density(gm/ml)

Tapped density(gm/ml)

Tapped density(gm/ml)

Carrs compressibility index (%)

Carrs compressibility index (%)

Hausner ratio

Hausner ratio

Angle of repose()

Angle of repose()

EVALUATION PARAMETERS OF TABLETS


Weight variation

Weight variation

Hardness (kg/cm2)

Hardness (kg/cm2)

Thickness (mm)

Thickness (mm)

Friability (%)

Friability (%)

Disintegration time (sec)

Disintegration time (sec)

Wetting time (sec)

Wetting time (sec)

% Drug content

% Drug content

Drug release (%) in 10 min

Drug release (%) in 10 min

Table 10: Comparison of Marketed Formulation with Optimized Formulation Prepared


by Direct Compression Method
Parameters

Marketed Preparation

Optimized formulation

Hardness(kg/cm2)

3.50.23

4.00.35

Disintegration time (sec)

240.75

200.92

Wetting time (sec)

290.89

260.95

Q10(% Drug release in 10 min)

98.893.12

99.492.87

Fig 13: Comparative Release Profile between Marketed Formulation and Optimized
Batch (F10)

% Drug release

100
80
60
40

Optimized Batch

20

Marketed Product

0
0

4
6
Time (mins)

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10

53

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

Similarity Factor

curves.

The

The similarity factor (f2) is a logarithmic

considered to be similar when f2 is

reciprocal square root transformation of

between

the sum of squared error and is a

calculated using equation of similarity was

measurement of the similarity in the

found to be 65.7. So, f2 value ensures

percent (%) dissolution between the two

sameness or equivalence of two curves.

50

dissolution

and

profiles

100.The

f2

are

value

Stability Study
Table 11: Stability Study of Optimized Formulation (F18) Carried out at 25 2oC/ 60
5 % RH
No. of

Disintegration

Wetting

Weeks

Time (sec)

Time(sec)

%Drug Content

Q10
(% Drug release in 10
min)

200.92

260.95

99.12 1.15

99.492.87

200.79

270.63

99.041.52

99.123.21

210.92

270.89

98. 951.32

98.563.18

220.98

270.73

98.651.21

98.122.59

220.83

290.79

98.441.29

97.393.26

All values are expressed as mean standard deviation, n=3


Table 12: Stability Study of Optimized Formulation (F18) Carried out at 40 2oC/ 75
5 % RH
No. of

Disintegration

Wetting

%Drug

Q10

Weeks

Time (sec)

Time

Content

(% Drug release in 10

(sec)

min)

200.92

260.95

99.121.15

99.492.87

210.52

270.63

98.901.30

98.912.59

220.92

280.89

98.621.24

97.563.21

220.72

290.73

98.151.15

96.122.81

230.81

300.79

97.821.17

96.023.08

All values are expressed as mean standard deviation, n=3


Stability study of ODT of Olanzapine was

the optimized formulation (F18) of ODT

carried out for 4 weeks at specified

revealed that no significant changes in the

condition. All data are mentioned in Table

physical parameters, disintegration time,

11 and Table 612. The stability studies of

wetting time, %drug content and % drug

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54

Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

release in 10

min when stored at

approach for rapid disintegrating tablet:

temperature and humidity conditions of 25

a review. Int J Pharma Res & Dev,

2oC/ 60 5 % RH and 40 2oC/ 75 5

3(3):17083.

% RH. So, we can say that formulation


having good stability.

2. Sharma, D., Kumar, D., Singh, M.,


Singh, G., Rathore, M. (2012). Fast
disintegrating tablets: a new era in

CONCLUSION
From the results obtained, it can be

novel drug delivery system and new

concluded that complex of Olanzapine

market opportunities. J Drug Del &

with cyclodextrin and PVP K 30

Therapeutics, 2(3):74-86.

markedly improved the solubility and

3. Tiwari, G., Pathak, A., Goyal, R.,

dissolution behaviour of Olanzapine. The 2

Jadaun, C., Shivhare, R., Sharma,

full factorial design applied in this study

K.(2012). Fast dissolving tablets: A

was used to provide details of the

novel approach to drug delivery. World

influence of independent variables on the

J of Pharma Res, 1(3):478-99.

responses. Thus concentration of CCS and

4. Thakur, R., Kashi, M. (2011). An

concentration of Kyron T 314 was selected

unlimited scope for novel formulations

as independent variable. From the results

as orally disintegrating systems: Present

of 2 full factorial designs revealed that

and future Prospects. J Applied Pharma

amount of CCS and amount of Kyron T

Sci, 1(1):13-19.

314 significantly affect the dependent

5. Limbachiya,

M.,

Agarwal,

M.,

variables, disintegration time and wetting

Sapariya, A., Soni, S. (2011). Solubility

time. It is thus concluded that by using

enhancement

response surface design, an optimum point

water soluble drugs-a review. Int J

can be reached in the shortest time with

Pharma Res & Dev, 4(4):71-86.

minimum efforts. The derived polynomial


equation
predicting

and
the

contour
values

plots
of

aid

in

selected

independent variables for the preparation


of optimum Olanzapine Orodispersible
tablets with desired properties.

techniques

of

poorly

6. Patil, K., Pal, R. (2012). Potentials of


Inclusion

Complex

with

special

Reference to Cyclodextrin. World J


Pharma Res, 1 (1):52-68.
7. Banal, P., Singh, R., Singh, A. (2010).
Recent trends of fast dissolving tabletan overview of formulation technology.

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Formulation Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility Enhancement Technique

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HOW TO CITE THIS ARTICLE


Chauhan, K., V., Kadliya, P., N., Patel, B., A., Patel, K., N., Patel, P., A. (2014). Formulation
Optimization and Evaluation of Orodispersible Tablets of an Antipsychotic Drug Using Solubility
Enhancement Technique Journal Club for Pharmaceutical Sciences (JCPS). 1(I), 33-57.

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57